Welcome to the IBRO 2023 Interactive Programme
S0001 - Mechanisms underlying sensory processing alterations in SYNGAP1 haploinsufficiency (ID 501)
Abstract
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Amongst the numerous genes associated with intellectual disability, SYNGAP1 stands out for its frequency and penetrance of loss-of-function variants found in patients, as well as the wide range of co-morbid disorders associated with its mutation. Most studies exploring the pathophysiological alterations caused by Syngap1 haploinsufficiency in mouse models have focused on cognitive problems and epilepsy; however, whether and to what extent sensory perception and processing are altered by Syngap1 haploinsufficiency is less clear. By performing EEG recordings in awake mice, we identified specific alterations in multiple aspects of auditory and visual processing, including increased baseline gamma oscillation power, increased theta/gamma phase amplitude coupling following stimulus presentation and abnormal neural entrainment in response to different sensory modality-specific frequencies. We further observed lack of habituation to repetitive auditory stimuli and abnormal deviant sound detection. Interestingly, we found that most of these alterations are present in human patients as well, thus making them strong candidates as translational biomarkers of sensory processing alterations associated with SYNGAP1/Syngap1 haploinsufficiency. Syngap1 is expressed by GABAergic cells, including parvalbumin- (PV+) and somatostatin-positive (SST+) interneurons. We thus asked whether and to what extent Syngap1 haploinsufficiency restricted to GABAergic interneurons contributed to sensory processing alterations. We further investigated whether the timing of haploinsufficiency onset was a critical determinant for these alterations. We found that most of the differences in auditory processing observed in Syngap1 heterozygous mice were recapitulated in conditional transgenic mice where Syngap1 haploinsufficiency started before birth. Conversely, postnatal reduction of Syngap1 expression in postnatal PV+ cells had minor effects. We are currently investigating how Syngap1 haploinsufficiency alters the cellular physiology of PV+ and SST+ interneurons.
Q&A (ID 927)
S0002 - Genomic mechanisms that normalize excitatory-inhibitory ratio to maintain sensory perception (ID 502)
Abstract
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The ability to adapt to and learn from novel experiences is essential for an animal’s survival, and key questions in neuroscience concern the underlying molecular, cellular and circuit mechanisms. Genes whose transcription is altered in response to changes in neural activity and to sensory and emotional experiences are required for the development of neurons and synapses and for experience-dependent processes such as memory formation. However, the circuit function of experience-induced transcription and of the underlying genomic mechanisms remain unknown: for example, what are the functions of experience-induced transcriptional networks in regulating information processing in neural circuits? And: do these genetic mechanisms indeed increase the plasticity of neural circuits or rather restrict it? In my talk, I will discuss my lab’s recent experiments in which we focus on the visual cortex of adult mice and combine a wide array of genomic, genetic, electrophysiological, imaging and behavioral approaches to address these fundamental questions in neuroscience.
Q&A (ID 928)
S0003 - GABAergic neuron dysfunction underlies impaired perceptual learning and sensory-overreactivity in Fragile X syndrome (ID 503)
Abstract
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Susceptibility to sensory distractors, the hallmark symptom of Autism spectrum disorders (ASD) and Fragile X syndrome (FXS), prevents adapting to distracting stimuli such as a noisy cart or blinking lights, can limit social interactions and delay learning; however there are no therapies that target distractor susceptibility. We have designed a novel distractor task, in a mouse model of FXS, to identify a brain area/circuit that can be a therapeutic target to alleviate distractor sensitivity. In the distractor task, experienced mice are unable to perform a task in the presence of distractors, thus capturing distractibility issues experienced by humans with FXS. An analogous task implemented in humans with FXS shows similar deficits, underscoring the translational impact of this study. Neural circuits in the frontal cortex have a huge influence on attending to selective stimuli while ignoring distractors, although the role of the frontal cortex in mediating susceptibility to distractors in FXS is unexplored. Using cutting-edge in vivo calcium imaging we found that the susceptibility to sensory distractors in Fmr1-/-mice correlates with disruption in the dynamic range of vasoactive intestinal peptide (VIP) activity. Our data suggests that a hypofunction in Anterior Cingulate Cortex (ACC) contributes to dysfunctional VIP cells. These findings provide novel insights into the circuit mechanism of distractor susceptibility and will fuel new paradigms in targeted treatment development for FXS and ASD.
Q&A (ID 929)
S0004 - Somatosensory abnormalities in genetic models of autism spectrum disorders (ID 538)
Abstract
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Sensory abnormalities are a common feature in autism spectrum disorders (ASD). Similarly, sensory deficits have been described in mice lacking ASD-associated genes. In our laboratory, we investigate somatosensory abnormalities in Cntnap2 and Shank3b mutant mice, two well-characterized mouse models of ASD. When compared to controls, both strains of mutant mice displayed impaired whisker-dependent discrimination in the textured novel object recognition test (tNORT). Shank3b but not Cntnap2 mutant mice also showed avoidance behavior responses to repetitive whisker stimulation. Impaired whisker-dependent behaviors were accompanied by altered c-fos mRNA induction following whisker stimulation, with Cntnap2 and Shank3b mutants showing c-fos mRNA up- and down-regulation within the primary somatosensory cortex (S1). The different c-fos mRNA induction profiles observed in the two mutant strains were paralleled by different connectivity within S1: resting-state fMRI revealed S1 hyper- and hypo-connectivity in Cntnap2 and Shank3b mutant mice, respectively. Preliminary data suggest that somatosensory abnormalities observed in Cntnap2 and Shank3b mutant mice are associated to neuroimmune dysfunction. Our data indicate that are Cntnap2 and Shank3b mutant mice are reliable models to investigate somatosensory abnormalities that characterize ASD.